Opioids might inhibit the release of neurotransmitters such as the Glutamate and the P substance released by the dorsal root ganglion at the level of the spinal and cerebral marrow through the activation of G proteins that inhibit the adenylate cyclase and regulate ionic canals through their bond to opioid receptors. In that context, three opioid receptors were established: mu, delta and kappa, which are metabotropic receptors that bond to the G protein, with different biomolecular structure, but with interrelated functions (Henriksen and Willoch, 2008; Bruijnzeel, 2009; Stein and Lang, 2009; Friedman and Nabong, 2020). These receptors can be found in high concentrations in supraspinal regions, such as the limbic area and regions related to neurohormonal secretion, as the hypothalamus, and most of these receptors are pre synaptic (Friedman and Nabong, 2020).

Agonist opioids of the delta and mu receptors present an analgesic action, while the agonist opioids of the delta receptor seem to present lesser side effects after long periods of use. Interestingly, the mu receptor is the main receptor for opioid agonists used in pain management (Friedman and Nabong, 2020). The kappa receptor, in turn, might induce dopamine release and cooperate with the development of hallucination and dysphoria behaviors, also, high concentrations of kappa receptors can be found in the spinal cord, and are thought to play a central role in the development of hyperalgesia. One can speculate that this might limit the development of drugs that interact with this receptor (Chavkin, 2011; Friedman and Nabong, 2020). Opioids show a high distribution volume and high liposolubility. Consequently, a short infusion bolus, for example, might have significant effects on plasma concentrations (Henriksen and Willoch, 2008; Bruijnzeel, 2009; Stein and Lang, 2009) (Figure 1). Moreover, some of these medicines present very short plasma half-lives such as the remifentanil and the alfentanil (Henriksen and Willoch, 2008; Bruijnzeel, 2009; Ammar et al., 2021).

Interestingly, the brainstream has a great concentration of Mu opioid receptors in areas involved with the control of breathing and the respiratory frequency, in which, if activated they may interfere of the process of breathing (Boom et al., 2012). Although the mechanism involved with respiratory depression is complex, opioids might increase hypercapnia and reduce tidal and minute volume, leading to slow and irregular breathing, which in severe cases can progress to fatal apnea (Leino et al., 1999; Boom et al., 2012). Furthermore, a great number of opioid receptors can be also found in the pre-Bötzinger complex, which is an important area related to the inspiration and has been recently described in humans. The activation of opioid receptors in this particular area might play a role in respiratory depression (Pattinson, 2008; Montandon et al., 2011; Schwarzacher et al., 2011; Boom et al., 2012) (Figure 2).

Unfortunately, opioids can also cause dependence due to their interaction with Mu receptors in the brain, resulting in activation of the reward mesolimbic system, which is also activated in several other daily activities such as sex and eating. The activation of the mesolimbic system, in turn, is responsible for the activation of the tegmental ventral area, located in the mesencephalon, which acts by releasing dopamine in the accumbens nucleus, which provides a feeling of pleasure (Kosten and George, 2002). Another factor that might result in dependence is the opioid action on the locus coeruleus. Normally, the locus coeruleus produces noradrenalin, an excitatory neurotransmitter that regulates several functions such as the respiratory frequency and blood pressure. However, opioids can act on the Mu receptors in this region, which reduces the noradrenalin secretion, leading to metabolic alteration that include reduced respiratory frequency and arterial pressure. As a consequence of the chronic ingestion of opioids, the locus coeruleus increases its noradrenalin secretion in an attempt to manage the opioid effect. Therefore, when a reduction in the concentration of opioids in the nervous system occurs and greater noradrenalin concentration is observed, several symptoms of the withdrawal syndrome such as anxiety and the presence of muscle cramps might appear (Kosten and George, 2002).

Regarding the physiological effects of opioids, we observed several positive points, as the mechanisms involved in analgesia, and those involved in the IMV. However, some negative points were also observed such as chest wall rigidity, which can increase the respiratory depression, and the mechanism related to opioid dependence.

Additionally, even if opioids belong to the same class of drugs, they present distinct pharmacodynamic, pharmacokinetic mechanisms and molecular structure (Table 1).

Pulmonary impairment is one of the main pathophysiological mechanisms of the COVID-19. Patients with this disease might present pain and suffering, not only due to the illness, but also as a result of invasive procedures such as the IMV, required by around 69% of the COVID-19 patients admitted in ICU (Devlin et al., 2018; Ammar et al., 2021; Chang et al., 2021). Analgesia, mainly using opioids, in this type of patients becomes usual, in order to provide them with comfort and also enable the accomplishment of further procedures such as orotracheal intubation (Allen et al., 2021). In the literature, opioids such as fentanyl, morphine, and hydromorphone are the main drugs used to treat ICU patients (Ammar et al., 2021). Our review summarizes the characteristics of the main opioids used in the treatment of COVID-19 patients (Table 1).

Fentanyl outstands as the most used opioid in the analgesia of conventional diseases. However, it is necessary to be cautious when using it through intravenous administration, since one of its main adverse effects is chest wall rigidity increase leading to respiratory depression (Roan et al., 2018; Ammar et al., 2021), which is recurrent in COVID-19 patients. Another drug that can be used to alleviate the discomfort caused by dyspnea is morphine (Ammar et al., 2021). Hydromorphone, in turn, can be used to substitute morphine or fentanyl, whenever the health service does not have the other medications, however, this opioid presents higher dosage error rate, when compared to other opioids, for this reason, health professionals must use it with caution to prevent overdoses of this medication (Ammar et al., 2021).

Other options of opioid analgesics for the treatment of COVID-19 patients include remifentanil, sufentanil, and alfentanil, which are drugs used in the hospital practice. However, they show some limitations that reduce their use in large scale situations. Remifentanil is associated to higher risk of hypotension, when compared to fentanyl, and has a shorter half-life, which might reduce the duration of its analgesic effect. Sufentanil and alfentanil are less frequently used in ICU also due to their short half-life. In addition, sufentanil might accumulate progressively when used in continuous and prolonged infusions. As for alfentanil, there are few reports of its use in continuous infusion by intensive care teams (Egan et al., 1993; Joshi et al., 2002; Ammar et al., 2021). However, these drugs are still considered options when the most commonly used drugs (morphine, hydromorphone, and fentanyl) are not available in the health service.

The advantages observed include the fact that many opioids such as fentanyl, hydromorphone, morphine, sufentanil, remifentanil, and alfentanil can be used in order to help in the IMV, and they are important to manage COVID-19 patients. However, since fentanyl is the most used opioid, the health care personnel might not have experience with the others, which might lead to dosage error. Also, sufentanil, remifentanil, and alfentanil show more limitations when compared to fentanyl, since they have a shorter half-life.

When managing COVID-19 patients, few drugs presented proved efficacy to modulate the outcome mainly regarding more severely affected individuals that required intensive care treatment and IMV. Among these drugs, dexamethasone and remdesivir reduced mortality risk and hospital care time, respectively (Beigel et al., 2020; RECOVERY Collaborative Group et al., 2021). However, other drugs such as opioids gained relevance in the COVID-19 pandemic for providing patients with greater comfort during treatment. Another fact to be taken into consideration is that since the start of the pandemic, Brazil has supported the acquisition of several drugs without scientific evidence for the COVID-19 treatment such as hydroxychloroquine, chloroquine and oseltamivir (Boschiero et al., 2021; MS-SUS COVID-19 Medications) spending around BRL 90 million to purchase such drugs (MS-SUS COVID-19 Medications). Curiously, the amount spent could have been used in the acquisition of other medicines, including opioids, which were missing in many healthcare centers in several parts of the country at certain times during the pandemic. As a result of the magnitude of the COVID-19 pandemic in Brazil, with approximately 22 million confirmed cases and over 600 thousand deaths [WHO Coronavirus (COVID-19) Dashboard] a variety of medicines, mainly opioids, were used to manage patients in ICU and under IMV.

In Brazil, around 80% of the population is assisted by the National Unified Health System (SUS, the Brazilian public health system), while the remaining population use private health care. Curiously, SUS is responsible for only 45% of the total expenditure with health in the country, while the private system accounts for 55%, this fact disagrees with the volume of assistance provided in each health sector (public and private) (SUS—20 years, 2021). Unfortunately, according to the Relação Nacional de Medicamentos Essenciais - Rename (Essential Medication National List), when it comes to opioids, only morphine and fentanyl are available for routine use at the SUS, and the small variety of drugs available can be explained, at least partly, by the low investment in this service (Rename, 2020). Therefore, the fact that the SUS that assists most of the population does not have enough resources to assist suitably those that requires this service is a matter of concern, mainly in a public health emergency situation such as that provoked by the COVID-19 pandemic.

As a consequence of the high use of opioids during the COVID-19 pandemic and public resource bad management, mainly by the federal government, there were reports of lack of opioids, as well as shortage of other medicines and inputs needed to perform intubation in Brazilian patients (Boschiero et al., 2021; Folha de São Paulo, 2021); and there were several reports of collapse in the health service. For example, according to the Associação Nacional de Hospitais Privados–ANAHP (Private Hospital National Association), on March 18, 2021, the institutions that are members of that association reported having a stock of fentanyl that would last only 20 days (ANAHP, 2021). Also, according to a survey carried out up to April 13, 2021 by the Federação das Santas Casas e Hospitais Beneficentes do Estado de São Paulo–Fehosp (Federation of Santa Casas and other charitable hospitals of São Paulo), around 160 hospitals had stocks of anesthetics and other medication needed for intubation that would only last from 3 to 5 days, with certain municipalities such as Guarujá and Rio Preto reporting even lower stocks that would probably end in 2 or 3 days (Fehosp–News). Such supply crisis affected and might still affect the combat to the pandemic in Brazil, preventing the treatment of patients that require intubation and potentially increasing dosage errors by the medical team, for not being acquainted with the use of the alternative medication available (Adams et al., 2020) or even, impairing the analgesia of those patients, preventing measures to alleviate their respiratory distress.

Unfortunately, the medication supply crisis in Brazil goes beyond opioids, several means of communication informed and are still informing that hospitals have low stocks of the “intubation kit,” that is, medication and necessary supplements to carry out orotracheal intubation (CNM, 2021; Folha de São Paulo, 2021). This fact might have contributed, at least partly, to the high mortality rate of patients in ICU throughout the country. In fact, the mortality rate among Brazilian patients with the COVID-19 disease in ICUs (∼55%), was higher than those of many other countries such as China (37.7%), Italy (25.6%), Spain (29.2%), United States of America (23.6%), Denmark (41.2%), Germany (24.3%), and the United Kingdom (8.0%) (Quah et al., 2020; Ranzani et al., 2021). The figures in Brazil were distributed differently among the states and regions of the country, with the highest death index, 79%, being observed in the Northern region of the country (Table 2).

Interestingly, up to October 20, 2021, Brazil used a total of 5,273,598 opioids in its five regions, with only three different types of opioids available in the SUS, and out of those morphine, fentanyl and remifentanil, accounted for, respectively, 559,270 (10.6%), 4,624,328 (87.6%) and, 90,000 (1.8%) units of opioids used. In our analysis, we also observed that many Brazilian regions with high number of confirmed cases of COVID-19 had few units of opioids available, as the Southeast region, with a 0.23 units of opioids per confirmed COVID-19 case, and the South region, with 0.05 units. Furthermore, taking into account the number of deaths due to COVID-19 and total opioids, these 2 Brazilian regions also presented the lowest index in the country, in which the Southeast had 6.90 opioids units per death due to COVID-19, and the South region accounted for 2.30 (Table 2). These two regions were the most affected by the COVID-19, presenting the highest numbers of cases and deaths, thus their opioid supply should have been increased in order to better manage the COVID-19 cases.

A Brazilian study on hospital analgesic consumption trends carried out from 2011 to 2015 showed that although a noticeable reduction in the public expenditure with analgesia occurred, the costs are still high, so that in the last year analyzed, the total cost of analgesics was 326,515€, and out of this total, 84,545€ were spent with analgesic opioids, which represents approximately 26% of the total cost (Monje et al., 2019).

It seems relevant to observe that Brazil has a lower prevalence of opioid use when compared to the United States of America or the rest of the world. One report from 2004 surveyed more than 15,000 individuals in the first and second grade of high schools and the prevalence of opioid use, at least once in lifetime, was 0.7% (ranging from 0.2% in Rio de Janeiro to 1.4% in Salvador) (Baltieri et al., 2004). Another report interviewed 8,589 Brazilians citizens aged between 12 and 65 years old, and the prevalence of opioid use was only 1.4% (Galduróz and Cebrid, 2003). Finally, the latest report on opioid use in Brazil observed an increased prevalence when compared to previous years, nearly 2.9% of the individuals surveyed stated that they had used opioids at least once in their lives (Krawczyk et al., 2020).

Regarding positive points, the federal government could distribute opioids to all Brazilian states, even with a logistic issue related to great distances and difficult access to some cities in the North. Also, Brazil seems to have a lower prevalence of opioid use disorder. On the negative side, we observed that the federal government distributed a low number of opioids to the Brazilian states, which might have predisposed some regions to shortage of opioids. Also, Brazil did not distribute the opioids taking the COVID-19 cases and deaths into account, which might have had an impact in the outcome of the public health policy of the states.

Although the management of sedation in critical patients in IMV is difficult, it is required during the therapeutical intervention. In high doses or for long periods, its use might result in undesirable effects such as the occurrence of delirium or acute cerebral disfunction, which are considered serious problems for the medical team and the patients’ families. European and American guidelines recommend that, in mechanically ventilated patients, sedation is dosed so that the patient can be awaken easily and at the same time has a competent analgesia, since this might reduce delirium incidence (Analgesia and Sedation in Covid, 2021; EMC, 2021; EMCDDA, 2021; Fehosp, 2021; MS-SUS COVID, 2021; Opioid Basics, 2021; Summary of, 2482, SUS, 2021; Understanding the Epidemic, 2021; WHO Coronavirus, 2021; Page, 2021; Pun et al., 2021). However, chronic and indiscriminate use of opioids might cause dependence as reported in the literature (Kosten and George, 2002). Nevertheless, their use in the COVID-19 pandemic is justifiable for the reasons listed above. Delirium incidence is highly prevalent and prolonged in COVID-19 patients and the use of benzodiazepines along with the absence of the family were modifiable risk factors identified in a multicenter study (Pun et al., 2021).

Patients with opioid dependence might be one of the most affected groups in the pandemic, since they are considered a risk population that is marginalized and require more personalized and constant care (Alexander et al., 2020). Several factors can be associated to the greater impact of the pandemic on this group, for example, a study in the South Africa reported that long periods of lockdown might increase the risk of overdose, since a reduction in the addicted individual’s tolerance occurs. In addition, those individuals might use other substances that are also nervous system depressants such as alcohol and benzodiazepines (Stowe et al., 2020; Thylstrup et al., 2020). Another relevant factor affecting this group is the shortage of methadone and buprenorphine, medicines used to treat opioid use disorder, since the delivery of this medication in the pandemic context might be harmed, which might have led to treatment discontinuation and a return to the use of illegal opioids (Magura and Rosenblum, 2001; Elliott et al., 2017; Sordo et al., 2017; Degenhardt et al., 2019; Gisev et al., 2019).

The United States of America and Europe perhaps are the regions that were most affected by opioid use disorders worldwide, and the COVID-19 might have played an important role in this health issue, as described below.

COVID-19 patients with pulmonary impairment also presented other symptoms such as dyspnea, which is a frequent clinical manifestation with repercussions at the physical and psychological levels causing suffering to the patient. Dyspnea mechanisms include: (i increase in the afferent signals of chemoreceptors and mechanoreceptors of the upper airways, lung, chest wall, and muscles of breathing; (ii increase in the respiratory effort sensation, and (iii dissociation between the ventilatory needs and the ventilation capacity (Burki and Lee, 2010)

One of the opioids main mechanisms of action in intubation is the reduction in the metabolic rate and ventilatory needs, decrease in the bulbar reflex to hypercapnia and hypoxia, respiratory center neurotransmission alteration, respiratory sensitization suppression, reduction in the respiratory drive, vasodilation, and anxiety reduction effects (Helms et al., 2020; Kapp et al., 2020; Pun et al., 2021). However, in COVID-19 patients, the strategies to prevent cough and dyspnea with the use of opioids might, many times, postpone the orotracheal intubation procedure and generate severe pulmonary consequences. In addition, the continuous use of opioids was associated with greater risk of patients in intensive care developing delirium, probably due to the fact that higher doses are prescribed, of both sedatives and analgesics, to COVID-19 patients, when compared to patients that did not have this disease (Helms et al., 2020; Kapp et al., 2020; Pun et al., 2021).

A quite trendy term these days is analgosedation, which consists in reaching sedation through the use of opioids before considering sedation through non-analgesic medication (Devlin et al., 2018; Adams et al., 2020). Throughout the pandemic, the use of analgesia and analgosedation was advisable in usual care (Riker et al., 2009; Adams et al., 2020). In the H1N1 virus pandemic, the use of fentanyl was higher in patients with pneumonia caused by the H1N1 virus or with acute respiratory distress syndrome associated with bacterial pneumonia (Olafson et al., 2012), showing that in the context of respiratory virus pandemics such as the current one, opioids are even more demanded. As exemplified, opioids play a relevant role in orotracheal intubation due to several factors. More specifically, fentanyl acts reducing the sympathetic nervous system, mainly reducing arterial pressure and causing respiratory depression (Allen et al., 2021).

However, opioids also present side effects such as diarrhea, hyperalgesia, dysphoria, tolerance and dependence processes, their prolonged use might be associated to immunological system suppression, and high doses of opioids might lead to respiratory depression, exacerbating the poor respiratory condition of those patients (Boom et al., 2012; Franchi et al., 2019; Cismaru et al., 2021). Patients with high doses of opioids might experience hypercapnia and hypoxia, due to the previously mentioned mechanisms, thus contributing to more severe respiratory symptoms (LeGrand et al., 2003; Ataei et al., 2020; Velavan and Meyer, 2020). Chronic use of opioids might lead to the induction of immune cell apoptosis, thymus and splint hypotrophy, and suppression of the proliferation of lymphocytes B and T, in addition to the leukocyte activity (Nabati et al., 2013; Ataei et al., 2020). Unfortunately, the lack of clinical studies on patients infected by the SARS-CoV-2 prevents a thorough evaluation of the possible side effects of the use of opioids during the pandemic (Drożdżal et al., 2020), and an analysis of the impact of the use of these drugs might only be possible after further observational studies are carried out.

Regarding the positive points of opioids in this topic, we could observe that opioids can be used in IMV in order to decrease patients’ pain and the anxiety in respiratory depression. They can also prevent asynchronous breath and reduce the respiratory drive, which is harmful to the patient, and optimize ventilation. However, some negative points were also observed, since the use of opioids might be also associated with increased chest wall rigidity, which can increase the respiratory depression of these patients. Some adverse effects of their use such as diarrhea, hyperalgesia, dysphoria, tolerance and dependence processes were also found, and their prolonged used might be associated with immune system impairment.